Despite significant advances in preventive therapies, CHD remains the leading cause of death in the United States. An elevated level of plasma LDL-C is the single most important risk factor for the development of this disease (16), and LDL-lowering forms the cornerstone of CHD prevention. During the last decade, PCSK9 (proprotein convertase subtilisin/kexin type 9) has emerged as a potent regulator of LDLR levels in liver, and thus of plasma LDL-C concentrations (17). We have shown that haploinsufficiency of PCSK9 due to loss-of-function mutations (18) is associated with a 28% reduction in plasma levels of LDL-C and an 88% reduction in cardiovascular events (2). The most compelling evidence of the importance of PCSK9 in plasma LDL-C metabolism is the finding that individuals with no circulating PCSK9 have exceedingly low plasma levels of LDL-C (-15 mg/dL) (19). To date, no adverse clinical sequela has been found in humans lacking PCSK9. These observations, which were made during the last funding period of this grant, established that blocking the action of PCSK9 is a viable and potent target for the treatment of hypercholesterolemia and the reduction of cardiovascular risk. As such, a complete characterization of the molecular mechanisms by which PCSK9 functions to degrade LDLRs is paramount.